1 Nature Reviews Genetics 2007 Vol: 8(2):126-138. DOI: 10.1038/nrg2042

Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility

Signalling through Frizzled (Fz)/planar cell polarity (PCP) is a conserved mechanism that polarizes cells along specific axes in a tissue. Genetic screens in Drosophila melanogaster pioneered the discovery of core PCP factors, which regulate the orientation of hairs on wings and facets in eyes. Recent genetic evidence shows that the Fz/PCP pathway is conserved in vertebrates and is crucial for disparate processes as gastrulation and sensory cell orientation. Fz/PCP signalling depends on complex interactions between core components, leading to their asymmetric distribution and ultimately polarized activity in a cell. Whereas several mechanistic aspects of PCP have been uncovered, the global coordination of this polarization remains debated.

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Figures
Figure 1: PCP and the organization of several tissues in a variety of systems.a–d | Proximal–distal orientation of hairs on appendages in Drosophila melanogaster and mouse. a | Wing cells of D. melanogaster generate an actin hair that points distally in wild-type cells. b | Mutations in planar cell polarity (PCP) genes disrupt this orientation and instead, wing hairs create swirls and waves (a fz mutant is shown). c,d | The pattern of mammalian fur/hairs, similar to D. melanogaster wing hairs, is regulated by frizzled (Fz)/PCP signalling. In fz mutant animals, hairs do not point uniformly distally but appear in swirls and waves (a wild-type and a Fz6 mutant mouse paw are shown in c and d, respectively). e–h | PCP aspects of sensory cell orientation. In the D. melanogaster eye (e,f) the ommatidia, or facets, are composed of photoreceptors, which are arranged in precisely oriented trapezoids (most evident by the rhabdomeres, the dark light harvesting organelles). In PCP mutants, both the arrangement of the photoreceptors in each ommatidium and the arrangement of ommatidia with respect to the whole eye become disorganized (a Stbm mutant is shown in f). Individual sensory hair cells of the mammalian (mouse) choclea (inner ear) generate polarized bundles of actin-based stereocilia (labelled in green through a phalloidin staining). In Fz/PCP mutants these bundles still form but their orientation becomes randomized (a wild-type and a looptail/Vangl2 mutant choclea are shown in g and h, respectively). i–l | PCP effects on convergent extension in vertebrate gastrulation and neurulation. Vertebrate (zebrafish) embryos from PCP mutants fail to extend their anteroposterior axis properly as cells do not migrate nor do they intercalate medially in a coordinated manner. This leads to a shortened and broadened phenotype (a lateral view and a dorsal view of zebrafish embryos are shown in i,j and k,l respectively; a wild-type and a trilobite/Stbm mutant are shown in i,k and j,l respectively. Images in panels c,d and g,h courtesy of J. Nathans, John Hopkins University, Baltimore, MA, and M. W. Kelley, National Institutes of Health, Bethesda, MD, USA, respectively. Images in panels i–l reproduced with permission from Nature (Ref. 54) © (2006) Macmillan Publishers Ltd. Figure 2: Subcellular distribution of core Fz/PCP factors in Drosophila melanogaster and vertebrates.a–c | Examples of cells with epithelial character (marked by grey shading). Drosophila melanogaster wing cells and eye R3 and R4 cells and mouse sensory hair cells in the cochlea (inner ear) are shown in a, b and c, respectively. d,e | Examples of dividing cells. The spindle orientation in the D. melanogaster sensory organ precursor (SOP) cells depends on the asymmetric distribution of the Frizzled (Fz)/planar cell polarity (PCP) factors (as shown in d), as does the orientation of neuroectodermal cells in zebrafish (as shown in e; note that during mitosis the asymmetric distribution of PK is lost and then re-established). Depending on the tissue, only a subset of the respective proteins has been analysed (the D. melanogaster wing is the only tissue in which all proteins were analysed; all but DSH have been analysed in the eye). These illustrations represent the localizations patterns of PCP proteins at the proposed time of signalling. In the wing, asymmetry of Flamingo (FMI) has been reported earlier, but the relevance of this is unknown82. Note that in the mouse inner ear (as shown in c) vang-like 2 (VANGL2) and FZ3/FZ6 localize to the same side of the cells; it is not known whether other Fz family members localize with the DSH homologues DVL1 and DVL2 to the opposite side. During zebrafish gastrulation (as shown in e) Prickle (Pk), which is represented by green circles, is cytoplasmic during cell division but regains polarity after separation of the daughter cell. Only PK has been analysed in this context, but its localization depends on the presence of Strabismus (STBM). Figure 3: The Fz/PCP pathway regulates cell motility during convergent extension and ommatidial rotation.a,b | Schematic representation of the cell–cell traction model of cell intercalation during convergent extension. In Xenopus laevis mesoderm bipolar cells show both medial and lateral protrusions (as shown in a), which enable cells to make contact and create traction by harnessing the actin cytoskeleton (represented through black lines). In addition cells might contact each other along their cell bodies, where the cell cortex (outlined in red) strengthens the cell against the pulling forces of opposing cells. In the neuroectoderm and mesoderm of zebrafish and in the neuroectoderm of X. laevis monopolar cells produce only medially directed protrusions (as shown in b); however, forces similar to those of bipolar cells might also be required for their migration. Planar cell polarity (PCP) signalling is thought to restrict protrusions to the mediolateral axis. During ommatidial rotation (as shown in c), PCP signalling in the R3 and R4 photoreceptor precursor cells might restrict dynamic rearrangements of cell adhesion (represented by a broken red line) to dictate the direction of rotation (inset describes the location of R3 and R4 in the five-cell precluster; arrows indicate the direction of rotation). The actin cytoskeleton is probably required to generate force during rotation. Cells of the photoreceptor precluster are outlined in black, whereas the surrounding epithelial cells are outlined in white. Red lines indicate cell adhesion through adherens junctions. As the precluster matures, more cells are recruited. In both the cases of convergent extension and ommatidial rotation it is thought that frizzled (Fz)/PCP signalling affects at least in part the motility process through E-cadherin. Figure 4: Activity slopes of Fz/PCP signalling and the FT–DS–FJ interactions in different Drosophila melanogaster tissues.Frizzled (Fz)/planar cell polarity (PCP) activity is indicated in violet and the Fat–Dachsous–Four-jointed (FT–DS–FJ) read-out in blue. a | Drosophila melanogaster eye. b | D. melanogaster wing. c | D. melanogaster abdomen. Note that in the distinct contexts a different relationship between the presumed FZ activity and FT–DS activity-gradients is observed, indicating a complicated relationship between the two PCP systems. The activity slopes are drawn as deduced from genetic experimental data for each tissue (see text for details). In the abdomen the anterior (A) and posterior (P) compartments (comp) have opposing FT–DS–FJ slopes.
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References
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    • . . . PCP was first recognized in the insects Oncopeltus fasciatus1 and Drosophila melanogaster2, 3, 4 . . .
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    • . . . PCP was first recognized in the insects Oncopeltus fasciatus1 and Drosophila melanogaster2, 3, 4 . . .
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    • . . . PCP was first recognized in the insects Oncopeltus fasciatus1 and Drosophila melanogaster2, 3, 4 . . .
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    • . . . PCP was first recognized in the insects Oncopeltus fasciatus1 and Drosophila melanogaster2, 3, 4 . . .
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    • . . . In particular, fmi and dgo, as key players in the core group of Fz/PCP factors, need to be taken into account in future modelling approaches, as has been already partially attempted6, 57, 58 . . .
    • . . . As the atypical cadherin FMI mediates homophilic interactions between neighbouring cells47, it could also mediate a 'functional' FZ–STBM interaction (see for an example the model in Refs 6, 58) . . .
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    • . . . This Fz-mediated pathway is distinct from canonical Wnt–Fz/-catenin signalling7, 9 . . .
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    • . . . This Fz-mediated pathway is distinct from canonical Wnt–Fz/-catenin signalling7, 9 . . .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
  10. Wallingford, J. B., Fraser, S. E. & Harland, R. M. Convergent extension: the molecular control of polarized cell movement during embryonic development. Dev. Cell 2, 695-706 (2002) , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
    • . . . Fz/PCP signalling establishes cell polarity that results in directed cell motility during ommatidial rotation (OR) of photoreceptor clusters in the D. melanogaster eye imaginal disc66, 67, 68 and in CE during vertebrate gastrulation and neurulation10, 11, 12, 23, 69 . . .
    • . . . For instance, the eye imaginal disc is a highly ordered epithelium, as the cells are connected by tight adhesive contacts and maintain uniform apical–basal polarity, whereas the mesodermal and neuroectodermal cells undergoing CE are mesenchymal in nature, having reduced adhesion between cells and an elongated cell shape showing leading edge polarity10, 11, 12, 23, 69 . . .
    • . . . In addition to DSH, orthologues of all D. melanogaster core Fz/PCP factors — STBM, PK, FZ, DGO (known as diversin in vertebrates), and FMI — have been implicated in CE10, 11, 12, 69 . . .
  11. Keller, R. Shaping the vertebrate body plan by polarized embryonic cell movements. Science 298, 1950-1954 (2002) , .
    • . . . The unifying theme of Fz/PCP signalling is cellular polarization; this is not limited to the epithelium but is also observed in mesenchymal cells, and the downstream effects vary (reviewed in Refs 6–9, 11, 12) . . .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
    • . . . The most studied of these is the role of Fz/PCP signalling during CE (Fig. 1i–l), which occurs in mesenchymal cells11, 12, 23 . . .
    • . . . Fz/PCP signalling establishes cell polarity that results in directed cell motility during ommatidial rotation (OR) of photoreceptor clusters in the D. melanogaster eye imaginal disc66, 67, 68 and in CE during vertebrate gastrulation and neurulation10, 11, 12, 23, 69 . . .
    • . . . In addition to DSH, orthologues of all D. melanogaster core Fz/PCP factors — STBM, PK, FZ, DGO (known as diversin in vertebrates), and FMI — have been implicated in CE10, 11, 12, 69 . . .
  12. Myers, D. C., Sepich, D. S. & Solnica-Krezel, L. Convergence and extension in vertebrate gastrulae: cell movements according to or in search of identity? Trends Genet. 18, 447-455 (2002) , .
    • . . . The unifying theme of Fz/PCP signalling is cellular polarization; this is not limited to the epithelium but is also observed in mesenchymal cells, and the downstream effects vary (reviewed in Refs 6–9, 11, 12) . . .
    • . . . The most studied of these is the role of Fz/PCP signalling during CE (Fig. 1i–l), which occurs in mesenchymal cells11, 12, 23 . . .
    • . . . Fz/PCP signalling establishes cell polarity that results in directed cell motility during ommatidial rotation (OR) of photoreceptor clusters in the D. melanogaster eye imaginal disc66, 67, 68 and in CE during vertebrate gastrulation and neurulation10, 11, 12, 23, 69 . . .
    • . . . The mechanisms of convergence differ between animal models and tissues; mesodermal cells of X. laevis elongate along the mediolateral axis and show bipolar protrusions, whereas cells of the neuroectoderm and zebrafish mesoderm show monopolar protrusions12, 23, 70, 71, 72, 73 (Fig. 3) . . .
    • . . . In addition to DSH, orthologues of all D. melanogaster core Fz/PCP factors — STBM, PK, FZ, DGO (known as diversin in vertebrates), and FMI — have been implicated in CE10, 11, 12, 69 . . .
  13. Bellaiche, Y., Beaudoin-Massiani, O., Stuttem, I. & Schweisguth, F. The planar cell polarity protein Strabismus promotes Pins anterior localization during asymmetric division of sensory organ precursor cells in Drosophila. Development 131, 469-478 (2004) , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
    • . . . Accordingly, some physical interactions between apical–basal determinants and Fz/PCP factors have been reported13, 45, 46. . . .
    • . . . In this case, PK and STBM localize to the anterior cortex, and FZ is enriched at the posterior cortex13, 14 (Fig. 2d), whereas FMI remains distributed uniformly around the SOP cell cortex49 . . .
  14. Bellaiche, Y., Gho, M., Kaltschmidt, J. A., Brand, A. H. & Schweisguth, F. Frizzled regulates localization of cell-fate determinants and mitotic spindle rotation during asymmetric cell division. Nature Cell Biol. 3, 50-57 (2001) , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
    • . . . In this case, PK and STBM localize to the anterior cortex, and FZ is enriched at the posterior cortex13, 14 (Fig. 2d), whereas FMI remains distributed uniformly around the SOP cell cortex49 . . .
  15. Goldstein, B., Takeshita, H., Mizumoto, K. & Sawa, H. Wnt signals can function as positional cues in establishing cell polarity. Dev. Cell 10, 391-396 (2006) , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
    • . . . Nevertheless recent data from Caenorhabditis elegans embryos show that a localized Wnt signal in the P2 cell, posterior-most blastomere, is required for the polarized positioning of the mitotic spindle in the EMS cell15, the progenitor of the endoderm and mesoderm, suggestive of instructive Wnt input . . .
    • . . . Further experiments that use localized Wnt expression to rescue PCP defects, as was done by genetic means in C. elegans (Ref. 15), will determine to what extent Wnt family members instruct the asymmetry of Fz/PCP signalling . . .
  16. Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173-177 (2003).This paper puts on the PCP map the polarization of the sensory cells in the mouse cochlea. A nice genetic study of the role of Vangl2/Stbm in the mouse , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
  17. Curtin, J. A. et al. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr. Biol. 13, 1129-1133 (2003) , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
  18. Montcouquiol, M., Crenshaw, E. B., 3rd & Kelley, M. W. Noncanonical Wnt signaling and neural polarity. Annu. Rev. Neurosci. 29, 363-386 (2006) , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
  19. Guo, N., Hawkins, C. & Nathans, J. Frizzled6 controls hair patterning in mice. Proc. Natl Acad. Sci. USA 101, 9277-9281 (2004).A knockout of the Fz6 gene showed 'classical' PCP defects in mouse fur, analogous to the defects in D. melanogaster wing or abdomen cuticle, showing the conserved PCP features in the epidermis of insects and mammals , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
  20. Park, T. J., Haigo, S. L. & Wallingford, J. B. Ciliogenesis defects in embryos lacking inturned or fuzzy function are associated with failure of planar cell polarity and Hedgehog signaling. Nature Genet. 38, 303-311 (2006) , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
  21. Simons, M. & Walz, G. Polycystic kidney disease: cell division without a c(l)ue? Kidney Int. 70, 854-864 (2006) , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
  22. Singla, V. & Reiter, J. F. The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 313, 629-633 (2006) , .
    • . . . Fz/PCP has also been implicated in the regulation of mitotic spindle orientation in invertebrates13, 14, 15 and in vertebrates the PCP pathway regulates many aspects of development including convergent extension (CE) and neural tube closure9, 10, 11, 12 (Fig. 1i–l), inner ear development16, 17, 18 (Fig. 1g,h), hair orientation in mammals19 (Fig. 1c,d), and ciliogenesis20, 21, 22 . . .
  23. Keller, R. et al. Mechanisms of convergence and extension by cell intercalation. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 355, 897-922 (2000) , .
    • . . . The most studied of these is the role of Fz/PCP signalling during CE (Fig. 1i–l), which occurs in mesenchymal cells11, 12, 23 . . .
    • . . . Fz/PCP signalling establishes cell polarity that results in directed cell motility during ommatidial rotation (OR) of photoreceptor clusters in the D. melanogaster eye imaginal disc66, 67, 68 and in CE during vertebrate gastrulation and neurulation10, 11, 12, 23, 69 . . .
    • . . . In addition, CE requires oriented and directed cell processes such as lamellipodia and filopodia23, but so far no such structures have been described in OR . . .
    • . . . The mechanisms of convergence differ between animal models and tissues; mesodermal cells of X. laevis elongate along the mediolateral axis and show bipolar protrusions, whereas cells of the neuroectoderm and zebrafish mesoderm show monopolar protrusions12, 23, 70, 71, 72, 73 (Fig. 3) . . .
  24. Adler, P. N., Krasnow, R. E. & Liu, J. Tissue polarity points from cells that have higher Frizzled levels towards cells that have lower Frizzled levels. Curr. Biol. 7, 940-949 (1997) , .
    • . . . This was shown through genetic means in the D. melanogaster wing, in which clonal overexpression of FZ caused wing hairs to orient away from the expression domain, whereas overexpression of STBM caused wing hairs to orient towards the expression region24, 25, 26, 27 . . .
  25. Bastock, R., Strutt, H. & Strutt, D. Strabismus is asymmetrically localised and binds to Prickle and Dishevelled during Drosophila planar polarity patterning. Development 130, 3007-3014 (2003) , .
    • . . . This was shown through genetic means in the D. melanogaster wing, in which clonal overexpression of FZ caused wing hairs to orient away from the expression domain, whereas overexpression of STBM caused wing hairs to orient towards the expression region24, 25, 26, 27 . . .
    • . . . In each cell, before the presumed onset of Fz/PCP signalling, all core Fz/PCP components are localized uniformly around the apical–lateral cortex25, 27, 38, 39, 40, 41, 42, partially overlapping with cellular junctions43 . . .
    • . . . Apical localization depends on the presence of the PCP transmembrane proteins FZ, STBM and FMI; in each mutant background the apical localization of the remaining PCP factors is lost or strongly reduced25, 27, 38, 39, 40, 41, 42, 44 . . .
    • . . . By contrast, the proteins that function as antagonists of FZ — PK and STBM — become enriched at the proximal side of wing cells25, 27 . . .
  26. Jenny, A., Reynolds-Kenneally, J., Das, G., Burnett, M. & Mlodzik, M. Diego and Prickle regulate Frizzled planar cell polarity signalling by competing for Dishevelled binding. Nature Cell Biol. 7, 691-697 (2005).Genetic and physical interactions between DGO, PK and DSH define that DGO and PK compete for DSH binding and that, in contrast to PK, DGO promotes DSH mediated Fz/PCP signalling , .
    • . . . This was shown through genetic means in the D. melanogaster wing, in which clonal overexpression of FZ caused wing hairs to orient away from the expression domain, whereas overexpression of STBM caused wing hairs to orient towards the expression region24, 25, 26, 27 . . .
    • . . . Factors required in R3, such as FZ and DGO, localize to the R3 side of the R3–R4 cell border, whereas FMI, a factor genetically required in both cells, localizes to both sides of the R3–R4 cell border26, 40, 41, 44, 48 . . .
  27. Tree, D. R. et al. Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling. Cell 109, 371-381 (2002).This paper analyses the role of PK and shows that it antagonizes DSH membrane localization. The potential feedback loops among the core PCP genes are proposed , .
    • . . . This was shown through genetic means in the D. melanogaster wing, in which clonal overexpression of FZ caused wing hairs to orient away from the expression domain, whereas overexpression of STBM caused wing hairs to orient towards the expression region24, 25, 26, 27 . . .
    • . . . In each cell, before the presumed onset of Fz/PCP signalling, all core Fz/PCP components are localized uniformly around the apical–lateral cortex25, 27, 38, 39, 40, 41, 42, partially overlapping with cellular junctions43 . . .
    • . . . By contrast, the proteins that function as antagonists of FZ — PK and STBM — become enriched at the proximal side of wing cells25, 27 . . .
  28. Ma, D., Yang, C. H., McNeill, H., Simon, M. A. & Axelrod, J. D. Fidelity in planar cell polarity signalling. Nature 421, 543-547 (2003) , .
    • . . . Whereas FT expression is uniform in most tissues, DS, which might modify FT activity, is expressed in a gradient in the eye and (to a lesser extent) in the wing, which has made this group an attractive candidate as an upstream polarizing signal for Fz/PCP28, 29, 30, 31, 32, 33, 34, 35 . . .
    • . . . In the wing28, 29, 30 (Fig. 4b), ft and ds mutant clones seem to affect the strength of the fz non-autonomous phenotype28, 92 (Box 2), but it is not clear whether any graded activity of the FT–DS system is required for normal PCP establishment in this tissue29, 30 . . .
    • . . . However, very little is known about their molecular functions or the regulatory interactions among themselves, with FJ, or with the Fz/PCP core factors, except that FT and DS show heterophilic cell-adhesion behaviour across membranes of neighbouring cells28, 29, 30 and that the FT cytoplasmic tail can interact with the transcriptional co-repressor ATRO37 . . .
  29. Matakatsu, H. & Blair, S. S. Interactions between Fat and Dachsous and the regulation of planar cell polarity in the Drosophila wing. Development 131, 3785-3794 (2004) , .
    • . . . Whereas FT expression is uniform in most tissues, DS, which might modify FT activity, is expressed in a gradient in the eye and (to a lesser extent) in the wing, which has made this group an attractive candidate as an upstream polarizing signal for Fz/PCP28, 29, 30, 31, 32, 33, 34, 35 . . .
    • . . . FT and DS also interact with FJ (Refs 34, 35), which possibly modifies the activity of DS29, 32, 33, 36 . . .
    • . . . In the wing28, 29, 30 (Fig. 4b), ft and ds mutant clones seem to affect the strength of the fz non-autonomous phenotype28, 92 (Box 2), but it is not clear whether any graded activity of the FT–DS system is required for normal PCP establishment in this tissue29, 30 . . .
  30. Matakatsu, H. & Blair, S. S. Separating the adhesive and signaling functions of the Fat and Dachsous protocadherins. Development 133, 2315-2324 (2006) , .
    • . . . Whereas FT expression is uniform in most tissues, DS, which might modify FT activity, is expressed in a gradient in the eye and (to a lesser extent) in the wing, which has made this group an attractive candidate as an upstream polarizing signal for Fz/PCP28, 29, 30, 31, 32, 33, 34, 35 . . .
    • . . . In the wing28, 29, 30 (Fig. 4b), ft and ds mutant clones seem to affect the strength of the fz non-autonomous phenotype28, 92 (Box 2), but it is not clear whether any graded activity of the FT–DS system is required for normal PCP establishment in this tissue . . .
  31. Rawls, A. S., Guinto, J. B. & Wolff, T. The cadherins Fat and Dachsous regulate dorsal/ventral signaling in the Drosophila eye. Curr. Biol 12, 1021-1026 (2002) , .
    • . . . Whereas FT expression is uniform in most tissues, DS, which might modify FT activity, is expressed in a gradient in the eye and (to a lesser extent) in the wing, which has made this group an attractive candidate as an upstream polarizing signal for Fz/PCP28, 29, 30, 31, 32, 33, 34, 35 . . .
    • . . . In the eye57, 93, 94, 95 (Fig. 4c) in ft and ds mutants, the asymmetry of Fz/PCP complexes is randomized, indicating that they influence the FZ signalling bias in the R3–R4 cell pair31, 33 . . .
  32. Simon, M. A. Planar cell polarity in the Drosophila eye is directed by graded Four-jointed and Dachsous expression. Development 131, 6175-6184 (2004) , .
    • . . . Whereas FT expression is uniform in most tissues, DS, which might modify FT activity, is expressed in a gradient in the eye and (to a lesser extent) in the wing, which has made this group an attractive candidate as an upstream polarizing signal for Fz/PCP28, 29, 30, 31, 32, 33, 34, 35 . . .
    • . . . The phenotypes of fj mutants do not show the same severity as ft or ds, indicating that fj modifies the activity of these proteins32, 34, 36 . . .
    • . . . FT and DS also interact with FJ (Refs 34, 35), which possibly modifies the activity of DS29, 32, 33, 36 . . .
    • . . . Strikingly, in the developing eye the expression of DS forms an inverse gradient respect to the presumed Fz/PCP activity gradient and is under the transcriptional control of Wingless (WG)–-catenin signalling33 (Fig. 4a), indicating a model in which WG regulates the graded expression of DS, therefore creating a Fz/PCP activity slope through the FT/DS input32, 33. . . .
  33. Yang, C., Axelrod, J. D. & Simon, M. A. Regulation of Frizzled by Fat-like cadherins during planar polarity signaling in the Drosophila compound eye. Cell 108, 675-688 (2002).This is the first paper to put the Fat-Dachsous (FT-DS) cadherins on the map in the context of PCP establishment. It indicates that the FT-DS interaction might influence FZ activity , .
    • . . . Whereas FT expression is uniform in most tissues, DS, which might modify FT activity, is expressed in a gradient in the eye and (to a lesser extent) in the wing, which has made this group an attractive candidate as an upstream polarizing signal for Fz/PCP28, 29, 30, 31, 32, 33, 34, 35 . . .
    • . . . Elegant genetic dissection of their PCP involvement in the D. melanogaster eye show that FT acts positively on FZ and that DS inhibits FT activity33 (Table 3) . . .
    • . . . FT and DS also interact with FJ (Refs 34, 35), which possibly modifies the activity of DS29, 32, 33, 36 . . .
    • . . . Strikingly, in the developing eye the expression of DS forms an inverse gradient respect to the presumed Fz/PCP activity gradient and is under the transcriptional control of Wingless (WG)–-catenin signalling33 (Fig. 4a), indicating a model in which WG regulates the graded expression of DS, therefore creating a Fz/PCP activity slope through the FT/DS input32, 33. . . .
    • . . . In the eye57, 93, 94, 95 (Fig. 4c) in ft and ds mutants, the asymmetry of Fz/PCP complexes is randomized, indicating that they influence the FZ signalling bias in the R3–R4 cell pair31, 33 . . .
  34. Zeidler, M. P., Perrimon, N. & Strutt, D. I. The four-jointed gene is required in the Drosophila eye for ommatidial polarity specification. Curr. Biol. 9, 1363-1372 (1999) , .
    • . . . Whereas FT expression is uniform in most tissues, DS, which might modify FT activity, is expressed in a gradient in the eye and (to a lesser extent) in the wing, which has made this group an attractive candidate as an upstream polarizing signal for Fz/PCP28, 29, 30, 31, 32, 33, 34, 35 . . .
    • . . . The phenotypes of fj mutants do not show the same severity as ft or ds, indicating that fj modifies the activity of these proteins32, 34, 36 . . .
    • . . . FT and DS also interact with FJ (Refs 34, 35), which possibly modifies the activity of DS29, 32, 33, 36 . . .
  35. Zeidler, M. P., Perrimon, N. & Strutt, D. I. Multiple roles for four-jointed in planar polarity and limb patterning. Dev. Biol. 228, 181-196 (2000) , .
    • . . . Whereas FT expression is uniform in most tissues, DS, which might modify FT activity, is expressed in a gradient in the eye and (to a lesser extent) in the wing, which has made this group an attractive candidate as an upstream polarizing signal for Fz/PCP28, 29, 30, 31, 32, 33, 34, 35 . . .
    • . . . FT and DS also interact with FJ (Refs 34, 35), which possibly modifies the activity of DS29, 32, 33, 36 . . .
  36. Strutt, H., Mundy, J., Hofstra, K. & Strutt, D. Cleavage and secretion is not required for Four-jointed function in Drosophila patterning. Development 131, 881-890 (2004) , .
    • . . . The phenotypes of fj mutants do not show the same severity as ft or ds, indicating that fj modifies the activity of these proteins32, 34, 36 . . .
    • . . . FT and DS also interact with FJ (Refs 34, 35), which possibly modifies the activity of DS29, 32, 33, 36 . . .
  37. Fanto, M. et al. The tumor-suppressor and cell adhesion molecule Fat controls planar polarity via physical interactions with Atrophin, a transcriptional co-repressor. Development 130, 763-774 (2003) , .
    • . . . In addition, the intracellular domain of FT interacts with the nuclear factor, Atrophin (ATRO; also known as Grunge, GUG), indicating that the FT–DS interaction could function through transcriptional regulation37. . . .
    • . . . However, very little is known about their molecular functions or the regulatory interactions among themselves, with FJ, or with the Fz/PCP core factors, except that FT and DS show heterophilic cell-adhesion behaviour across membranes of neighbouring cells28, 29, 30 and that the FT cytoplasmic tail can interact with the transcriptional co-repressor ATRO37 . . .
  38. Axelrod, J. D. Unipolar membrane association of Dishevelled mediates Frizzled planar cell polarity signaling. Genes Dev. 15, 1182-1187 (2001) , .
    • . . . In each cell, before the presumed onset of Fz/PCP signalling, all core Fz/PCP components are localized uniformly around the apical–lateral cortex25, 27, 38, 39, 40, 41, 42, partially overlapping with cellular junctions43 . . .
    • . . . In the wing, the FZ–DSH–DGO factors become specifically enriched at the distal side of the cells38, 39, 42 (Fig. 2a; Table 1) . . .
  39. Das, G., Jenny, A., Klein, T. J., Eaton, S. & Mlodzik, M. Diego interacts with Prickle and Strabismus/Van Gogh to localize planar cell polarity complexes. Development 131, 4467-4476 (2004) , .
    • . . . In each cell, before the presumed onset of Fz/PCP signalling, all core Fz/PCP components are localized uniformly around the apical–lateral cortex25, 27, 38, 39, 40, 41, 42, partially overlapping with cellular junctions43 . . .
    • . . . Although the absence of DSH, PK, or DGO alone does not affect apical localization of other Fz/PCP factors, several double mutant combinations do (for example, pk-/- dgo-/- double mutants)39 . . .
    • . . . In the wing, the FZ–DSH–DGO factors become specifically enriched at the distal side of the cells38, 39, 42 (Fig. 2a; Table 1) . . .
    • . . . In the eye an analogous localization is observed along the border of the R3 and R4 photoreceptor precursor cells, where FZ–DGO are enriched apicolaterally on the polar side of R3 (and absent from the equatorial side of R4), whereas STBM–PK are localized on the equatorial R4 side and absent from the polar side of R3 (Refs 39, 41; Fig. 2b) . . .
  40. Das, G., Reynolds-Kenneally, J. & Mlodzik, M. The atypical cadherin Flamingo links Frizzled and Notch signaling in planar polarity establishment in the Drosophila eye. Dev. Cell 2, 655-666 (2002) , .
    • . . . In each cell, before the presumed onset of Fz/PCP signalling, all core Fz/PCP components are localized uniformly around the apical–lateral cortex25, 27, 38, 39, 40, 41, 42, partially overlapping with cellular junctions43 . . .
    • . . . Factors required in R3, such as FZ and DGO, localize to the R3 side of the R3–R4 cell border, whereas FMI, a factor genetically required in both cells, localizes to both sides of the R3–R4 cell border26, 40, 41, 44, 48 . . .
  41. Strutt, D., Johnson, R., Cooper, K. & Bray, S. Asymmetric localization of frizzled and the determination of Notch-dependent cell fate in the Drosophila eye. Curr. Biol. 12, 813-824 (2002) , .
    • . . . In each cell, before the presumed onset of Fz/PCP signalling, all core Fz/PCP components are localized uniformly around the apical–lateral cortex25, 27, 38, 39, 40, 41, 42, partially overlapping with cellular junctions43 . . .
    • . . . In the eye an analogous localization is observed along the border of the R3 and R4 photoreceptor precursor cells, where FZ–DGO are enriched apicolaterally on the polar side of R3 (and absent from the equatorial side of R4), whereas STBM–PK are localized on the equatorial R4 side and absent from the polar side of R3 (Refs 39, 41; Fig. 2b) . . .
    • . . . Factors required in R3, such as FZ and DGO, localize to the R3 side of the R3–R4 cell border, whereas FMI, a factor genetically required in both cells, localizes to both sides of the R3–R4 cell border26, 40, 41, 44, 48 . . .
  42. Strutt, D. I. Asymmetric localization of frizzled and the establishment of cell polarity in the Drosophila wing. Mol. Cell 7, 367-375 (2001).This work shows the asymmetric localization of FZ (as a FZ-GFP transgene) to one side of a wing cell undergoing Fz/PCP signalling. Further works followed this example for the other core PCP factors , .
    • . . . In each cell, before the presumed onset of Fz/PCP signalling, all core Fz/PCP components are localized uniformly around the apical–lateral cortex25, 27, 38, 39, 40, 41, 42, partially overlapping with cellular junctions43 . . .
    • . . . In the wing, the FZ–DSH–DGO factors become specifically enriched at the distal side of the cells38, 39, 42 (Fig. 2a; Table 1) . . .
  43. Wu, J., Klein, T. J. & Mlodzik, M. Subcellular localization of frizzled receptors, mediated by their cytoplasmic tails, regulates signaling pathway specificity. PLoS Biol. 2, 1004-1014 (2004).This paper shows that FZ has to be localized apically as a prerequisite for its function in PCP signalling. It maps the sequences associated/required for the apical localization of FZ , .
    • . . . In each cell, before the presumed onset of Fz/PCP signalling, all core Fz/PCP components are localized uniformly around the apical–lateral cortex25, 27, 38, 39, 40, 41, 42, partially overlapping with cellular junctions43 . . .
    • . . . On the basis of functional studies, it is known that polarization of the Fz/PCP components along the apical–basal axis is a prerequisite for their subsequent polarization along other axes, such as the proximal–distal one, and for Fz/PCP signalling itself43 . . .
  44. Jenny, A., Darken, R. S., Wilson, P. A. & Mlodzik, M. Prickle and Strabismus form a functional complex to generate a correct axis during planar cell polarity signaling. EMBO J. 22, 4409-4420 (2003) , .
    • . . . Apical localization depends on the presence of the PCP transmembrane proteins FZ, STBM and FMI; in each mutant background the apical localization of the remaining PCP factors is lost or strongly reduced25, 27, 38, 39, 40, 41, 42, 44 . . .
    • . . . Factors required in R3, such as FZ and DGO, localize to the R3 side of the R3–R4 cell border, whereas FMI, a factor genetically required in both cells, localizes to both sides of the R3–R4 cell border26, 40, 41, 44, 48 . . .
  45. Djiane, A., Yogev, S. & Mlodzik, M. The apical determinants aPKC and dPatj regulate Frizzled-dependent planar cell polarity in the Drosophila eye. Cell 121, 621-631 (2005) , .
    • . . . Accordingly, some physical interactions between apical–basal determinants and Fz/PCP factors have been reported13, 45, 46. . . .
    • . . . It is tempting to speculate that PP2A is required to keep FZ in a dephosphorylated state preventing the atypical Protein kinase C (aPKC), which is often found in association with the Partitioning (PAR) defective proteins 3 and 6 (PAR3 and PAR6), from inactivating FZ through phosphorylation45 . . .
    • . . . During PCP establishment in the eye, FZ levels are selectively increased in the R3–R4 pair by PAR3 (also known as Bazooka), which prevents aPKC from phosphorylating and inactivating FZ (Ref 45) . . .
    • . . . If these events occur 'universally', then it would seem that there is an antagonistic interaction between the complexes containing aPKC and FZ, which would be analogous to what occurs in the D. melanogaster eye45 . . .
  46. Montcouquiol, M. et al. Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals. J. Neurosci. 26, 5265-5275 (2006) , .
    • . . . Accordingly, some physical interactions between apical–basal determinants and Fz/PCP factors have been reported13, 45, 46. . . .
    • . . . In the cochlea, sensory cells are polarized from the inner to the outer edge; stainings with antibodies raised against these factors show that DSH localizes to the outer cell cortex where the actin-rich stereocilia form50 (Fig. 2c), whereas VANGL2 (the product of the Stbm mouse orthologue) localizes to the opposing, inner side of sensory cells46 . . .
    • . . . Intriguingly however, FZ3 and FZ6 co-localize with VANGL2 (Refs 46, 51), the opposite of what one would predict from the D. melanogaster data . . .
  47. Usui, T. et al. Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell 98, 585-595 (1999) , .
    • . . . FMI becomes enriched at both ends of each wing cell, proximally and distally, possibly stabilizing both complexes through its homophilic cell-adhesion behaviour47 . . .
    • . . . As the atypical cadherin FMI mediates homophilic interactions between neighbouring cells47, it could also mediate a 'functional' FZ–STBM interaction (see for an example the model in Refs 6, 58) . . .
  48. Wolff, T. & Rubin, G. M. Strabismus, a novel gene that regulates tissue polarity and cell fate decisions in Drosophila. Development 125, 1149-1159 (1998) , .
    • . . . Factors required in R3, such as FZ and DGO, localize to the R3 side of the R3–R4 cell border, whereas FMI, a factor genetically required in both cells, localizes to both sides of the R3–R4 cell border26, 40, 41, 44, 48 . . .
  49. Lu, B., Usui, T., Uemura, T., Jan, L. & Jan, Y. N. Flamingo controls the planar polarity of sensory bristles and asymmetric division of sensory organ precursors in Drosophila. Curr. Biol. 9, 1247-1250 (1999) , .
    • . . . In this case, PK and STBM localize to the anterior cortex, and FZ is enriched at the posterior cortex13, 14 (Fig. 2d), whereas FMI remains distributed uniformly around the SOP cell cortex49 . . .
  50. Wang, J. et al. Regulation of polarized extension and planar cell polarity in the cochlea by the vertebrate PCP pathway. Nature Genet. 37, 980-985 (2005) , .
    • . . . In the cochlea, sensory cells are polarized from the inner to the outer edge; stainings with antibodies raised against these factors show that DSH localizes to the outer cell cortex where the actin-rich stereocilia form50 (Fig. 2c), whereas VANGL2 (the product of the Stbm mouse orthologue) localizes to the opposing, inner side of sensory cells46 . . .
  51. Wang, Y., Guo, N. & Nathans, J. The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells. J. Neurosci. 26, 2147-2156 (2006) , .
    • . . . Intriguingly however, FZ3 and FZ6 co-localize with VANGL2 (Refs 46, 51), the opposite of what one would predict from the D. melanogaster data . . .
  52. Wallingford, J. B. et al. Dishevelled controls cell polarity during Xenopus gastrulation. Nature 405, 81-85 (2000) , .
    • . . . Initial studies in X. laevis have indicated that DSH is enriched at the membrane at both ends of the mediolateral axis in cells undergoing CE movements52, 53 . . .
    • . . . Consistently, the expression of inhibitory forms of DSH or the overexpression of wild-type DSH in explants from X. laevis, leads to defects in either the stability or orientation of cell protrusions, both resulting in CE defects52 . . .
  53. Kinoshita, N., Iioka, H., Miyakoshi, A. & Ueno, N. PKC is essential for Dishevelled function in a noncanonical Wnt pathway that regulates Xenopus convergent extension movements. Genes Dev. 17, 1663-1676 (2003) , .
    • . . . Initial studies in X. laevis have indicated that DSH is enriched at the membrane at both ends of the mediolateral axis in cells undergoing CE movements52, 53 . . .
    • . . . Moreover, DSH localization analysis during CE in the dorsal marginal zone cells64 indicates that, similar to XGAP, it is also associated with mediolateral ends of cells53 . . .
  54. Ciruna, B., Jenny, A., Lee, D., Mlodzik, M. & Schier, A. F. Planar cell polarity signalling couples cell division and morphogenesis during neurulation. Nature 439, 220-224 (2006).The first data set to analyse PCP protein distribution in in vivo time-lapse movies in vertebrates. In combination with the genetic power of zebrafish this is the best reference for PCP factor localization during CE , .
    • . . . Images in panels i–l reproduced with permission from Nature (Ref. 54) © (2006) Macmillan Publishers Ltd. . . .
    • . . . Recently, during zebrafish neurulation Pk (GFP–Pk) has been found to localize to the membrane on the anterior side of cells in the notochord and neuroectoderm54, indicating that the Fz/PCP factors show asymmetric enrichments in the anteroposterior axis during neurulation . . .
    • . . . In maternal/zygotic trilobite (tri) mutants (tri is the zebrafish orthologue of Stbm; Table 1), Pk is lost from the membrane and detected uniformly in the cytoplasm54 . . .
    • . . . The enrichment of Pk at the anterior membrane also depends on Wnt–Fz activity as shown by a wnt5(ppt) wnt11(slb) double mutant in which wnt4 expression is knocked down, to eliminate the expression of the three Wnt genes54; wnt5 and wnt11 are considered the main non-canonical PCP-specific Wnt family members in this context (Table 2) . . .
    • . . . What is the relationship between the XGAP–PAR protein complex and the Fz/PCP factors? Although it requires the comparison of two different systems — mesoderm in X. laevis64 versus neuroectoderm in zebrafish54 — it is intriguing to speculate . . .
    • . . . In zebrafish mesenchymal cells undergoing CE, Pk is localized to the anterior end54, whereas, in X. laevis, the XGAP–PAR–aPKC complex is localized to the mediolateral ends during CE . . .
  55. Jiang, D., Munro, E. M. & Smith, W. C. Ascidian prickle regulates both mediolateral and anterior-posterior cell polarity of notochord cells. Curr. Biol. 15, 79-85 (2005) , .
    • . . . During gastrulation and notochord extension in the ascidian Ciona savignyi embryo, both PK and DSH are first seen in all membranes of presumptive notochord cells except at the membranes that touch the neighbouring muscle cells55 . . .
    • . . . Later PK (and STBM) are detected at the anterior end of each notochord cell, whereas DSH is found enriched at the lateral membrane (adjacent to the muscle cells)55, indicating that anterior localization of PK in the notochord is conserved . . .
    • . . . A further note of caution comes from the PCP factor localization studies in the notochord of C. savignyi, in which PK and STBM are localized to the anterior end of cells and DSH is found at the lateral ends after intercalation is completed55 . . .
  56. Amonlirdviman, K. et al. Mathematical modeling of planar cell polarity to understand domineering nonautonomy. Science 307, 423-426 (2005).This work provides the first mathematical modelling of PCP establishment in the D. melanogaster wing. It serves a starting point for future models , .
    • . . . It has been proposed, on the basis of biochemical and genetic data, that four of the Fz/PCP members (fz, dsh, Stbm, and pk) are sufficient to establish and maintain asymmetries in protein localization in D. melanogaster wing cells along with an initial asymmetry possibly generated by fat, ds, and fj (see below)56 . . .
    • . . . However, the model requires the interaction of FZ with STBM across cell membranes, which is purely speculative56 . . .
  57. Lawrence, P. A., Casal, J. & Struhl, G. Cell interactions and planar polarity in the abdominal epidermis of Drosophila. Development 131, 4651-4664 (2004).This work defines the PCP features of the abdominal cuticle of D. melanogaster in a detailed manner , .
    • . . . In particular, fmi and dgo, as key players in the core group of Fz/PCP factors, need to be taken into account in future modelling approaches, as has been already partially attempted6, 57, 58 . . .
    • . . . In the eye57, 93, 94, 95 (Fig. 4c) in ft and ds mutants, the asymmetry of Fz/PCP complexes is randomized, indicating that they influence the FZ signalling bias in the R3–R4 cell pair31, 33 . . .
  58. Le Garrec, J. F., Lopez, P. & Kerszberg, M. Establishment and maintenance of planar epithelial cell polarity by asymmetric cadherin bridges: a computer model. Dev. Dyn. 235, 235-246 (2006) , .
    • . . . In particular, fmi and dgo, as key players in the core group of Fz/PCP factors, need to be taken into account in future modelling approaches, as has been already partially attempted6, 57, 58 . . .
  59. Klein, T. J., Jenny, A., Djiane, A. & Mlodzik, M. CKI/discs overgrown promotes both Wnt-Fz/-catenin and Fz/PCP signaling in Drosophila. Curr. Biol. 16, 1337-1343 (2006) , .
    • . . . Recently, Casein kinase 1 (CK1; also known as Discs overgrown, DCO) has been added as a potential regulator of Fz/PCP factors in D. melanogaster59, 60 and a related PCP function in vertebrates has been proposed61 (Table 2) . . .
    • . . . CK1 can phosphorylate DSH in vitro and is required for DSH phosphorylation in vivo, although existing data indicate that CK1 kinase activity is not essential in the PCP context59, 60 . . .
    • . . . Genetic interactions between CK1 and fz/dsh indicate that CK1 acts positively on their activity59, 60 . . .
    • . . . In summary, CK1 is likely to function as a positive regulator of FZ and DSH activity in both Fz/PCP and canonical Wnt–Fz signalling59, 60. . . .
  60. Strutt, H., Price, M. A. & Strutt, D. Planar polarity is positively regulated by casein kinase I in Drosophila. Curr. Biol. 16, 1329-1336 (2006) , .
    • . . . Recently, Casein kinase 1 (CK1; also known as Discs overgrown, DCO) has been added as a potential regulator of Fz/PCP factors in D. melanogaster59, 60 and a related PCP function in vertebrates has been proposed61 (Table 2) . . .
    • . . . Whereas CK1 is apically enriched, it is not asymmetrically localized in the proximal–distal axis in wing cells, but in CK1 mutant tissue DSH becomes mislocalized60 . . .
  61. McKay, R. M., Peters, J. M. & Graff, J. M. The casein kinase I family: roles in morphogenesis. Dev. Biol. 235, 378-387 (2001) , .
    • . . . Recently, Casein kinase 1 (CK1; also known as Discs overgrown, DCO) has been added as a potential regulator of Fz/PCP factors in D. melanogaster59, 60 and a related PCP function in vertebrates has been proposed61 (Table 2) . . .
  62. Katanaev, V. L., Ponzielli, R., Semeriva, M. & Tomlinson, A. Trimeric G protein-dependent frizzled signaling in Drosophila. Cell 120, 111-122 (2005) , .
    • . . . The Go subunit of heterotrimeric G proteins is also required for Fz/PCP and canonical Wnt–Fz signalling62 . . .
    • . . . During PCP generation in wing cells, it shows a diffuse but proximally enriched apical localization62 . . .
  63. Hannus, M., Feiguin, F., Heisenberg, C. P. & Eaton, S. Planar cell polarization requires Widerborst, a B' regulatory subunit of protein phosphatase 2A. Development 129, 3493-3503 (2002) , .
    • . . . Moreover, the B subunit of Protein phosphatase 2A (PP2A), known as Widerborst (WDB) in D. melanogaster, is thought to target PP2A to its substrates and therefore, to confer substrate specificity, it localizes asymmetrically to apical junctions in a diffuse web of microtubules in the distal end of cells63 . . .
    • . . . The localization of WDB precedes the asymmetric localization of the Fz/PCP proteins and the expression of a dominant negative form of WDB results in uniform localization of Fz/PCP proteins63 . . .
  64. Hyodo-Miura, J. et al. XGAP, an ArfGAP, is required for polarized localization of PAR proteins and cell polarity in Xenopus gastrulation. Dev. Cell 11, 69-79 (2006) , .
    • . . . A recent study has identified physical interactions between the ADP ribosylation factor GTPase activating protein (ArfGAP), known in X. laevis as XGAP, and several PAR proteins as essential in the CE context64 . . .
    • . . . What is the relationship between the XGAP–PAR protein complex and the Fz/PCP factors? Although it requires the comparison of two different systems — mesoderm in X. laevis64 versus neuroectoderm in zebrafish54 — it is intriguing to speculate . . .
    • . . . Moreover, DSH localization analysis during CE in the dorsal marginal zone cells64 indicates that, similar to XGAP, it is also associated with mediolateral ends of cells53 . . .
    • . . . Reduction of XGAP disrupts the orientation of cell protrusions64 . . .
  65. Ossipova, O., Dhawan, S., Sokol, S. & Green, J. B. Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development. Dev. Cell 8, 829-841 (2005) , .
    • . . . Although this model is attractive and consistent with some known interactions such as those of the PAR1 kinase (PAR1 can phosphorylate and positively regulate DSH during CE65 and its localization seems to be mutually exclusive with that of aPKC/PAR3/PAR6 in several cellular contexts), other data are not in agreement and therefore this model remains speculative . . .
  66. Brown, K. E. & Freeman, M. EGFR signalling defines a protective function for ommatidial orientation in the Drosophila eye. Development 130, 5401-5412 (2003) , .
    • . . . Fz/PCP signalling establishes cell polarity that results in directed cell motility during ommatidial rotation (OR) of photoreceptor clusters in the D. melanogaster eye imaginal disc66, 67, 68 and in CE during vertebrate gastrulation and neurulation10, 11, 12, 23, 69 . . .
    • . . . In addition to the PCP pathway, OR is also regulated by the Epidermal growth factor receptor (EGFR), Notch, and other pathways66, 67, 80, 81, 82 . . .
  67. Gaengel, K. & Mlodzik, M. EGFR signaling regulates ommatidial rotation and cell motility in the Drosophila eye via MAPK/Pnt signaling and the Ras effector Canoe/AF6. Development 130, 5413-5423 (2003) , .
    • . . . Fz/PCP signalling establishes cell polarity that results in directed cell motility during ommatidial rotation (OR) of photoreceptor clusters in the D. melanogaster eye imaginal disc66, 67, 68 and in CE during vertebrate gastrulation and neurulation10, 11, 12, 23, 69 . . .
    • . . . In addition to the PCP pathway, OR is also regulated by the Epidermal growth factor receptor (EGFR), Notch, and other pathways66, 67, 80, 81, 82 . . .
    • . . . Interactions between the PCP and EGFR pathways during OR have been shown as both fz and fmi genetically interact with components of EGFR signalling, and the localization of FMI and FZ (FZ–GFP) is disrupted in backgrounds in which EGFR signalling is perturbed67, 82 . . .
  68. Wolff, T. & Ready, D. F. The beginning of pattern formation in the Drosophila compound eye: the morphogenetic furrow and the second mitotic wave. Development 113, 841-850 (1991) , .
    • . . . Fz/PCP signalling establishes cell polarity that results in directed cell motility during ommatidial rotation (OR) of photoreceptor clusters in the D. melanogaster eye imaginal disc66, 67, 68 and in CE during vertebrate gastrulation and neurulation10, 11, 12, 23, 69 . . .
    • . . . In the D. melanogaster eye disc, cells that are specified to become photoreceptors form a tightly associated cluster and, as a group, undergo a 90° rotation in the plane of the epithelium68, 78, 79 (Fig. 3) . . .
  69. Wallingford, J. B. Vertebrate gastrulation: polarity genes control the matrix. Curr. Biol. 15, R414-R416 (2005) , .
    • . . . Fz/PCP signalling establishes cell polarity that results in directed cell motility during ommatidial rotation (OR) of photoreceptor clusters in the D. melanogaster eye imaginal disc66, 67, 68 and in CE during vertebrate gastrulation and neurulation10, 11, 12, 23, 69 . . .
    • . . . In addition to DSH, orthologues of all D. melanogaster core Fz/PCP factors — STBM, PK, FZ, DGO (known as diversin in vertebrates), and FMI — have been implicated in CE10, 11, 12, 69 . . .
  70. Elul, T. & Keller, R. Monopolar protrusive activity: a new morphogenic cell behavior in the neural plate dependent on vertical interactions with the mesoderm in Xenopus. Dev. Biol. 224, 3-19 (2000) , .
    • . . . The mechanisms of convergence differ between animal models and tissues; mesodermal cells of X. laevis elongate along the mediolateral axis and show bipolar protrusions, whereas cells of the neuroectoderm and zebrafish mesoderm show monopolar protrusions12, 23, 70, 71, 72, 73 (Fig. 3) . . .
  71. Shih, J. & Keller, R. Cell motility driving mediolateral intercalation in explants of Xenopus laevis. Development 116, 901-914 (1992) , .
    • . . . The mechanisms of convergence differ between animal models and tissues; mesodermal cells of X. laevis elongate along the mediolateral axis and show bipolar protrusions, whereas cells of the neuroectoderm and zebrafish mesoderm show monopolar protrusions12, 23, 70, 71, 72, 73 (Fig. 3) . . .
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    • . . . The mechanisms of convergence differ between animal models and tissues; mesodermal cells of X. laevis elongate along the mediolateral axis and show bipolar protrusions, whereas cells of the neuroectoderm and zebrafish mesoderm show monopolar protrusions12, 23, 70, 71, 72, 73 (Fig. 3) . . .
    • . . . The mechanisms behind this difference are not clear, however regulation of both mechanisms relies on Fz/PCP signalling. wnt5 and wnt11 act through the Fz/PCP pathway in this context and loss of function (using the zebrafish mutants ppt and slb), and overexpression disrupt CE73, 74 . . .
    • . . . In zebrafish, a specific mesoderm population, the prechordal plate progenitors, contributes to axis extension through anteriorly directed migration73 . . .
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